Abstract: Background: Depression is a common manifestation of chronic illness, including cancer. Depression has been shown to be predictive of cancer progression, which is promoted via epithelial-mesenchymal transition (EMT) through high expression of Twist1, a helix-loop-helix transcription factor. However, the role of Twist1 in the brain and whether it involves in the pathophysiology of depression remains poorly understood. Methods: Depression model was made by chronic social defeat stress (CSDS) and multiple behavioral tests, gene manipulations and molecular biological analysis were applied. Results: We found that chronic stress elevated Twist1 expression in the medial prefrontal cortex (mPFC) of the vulnerable animals, which was reversed by fluoxetine treatment. Overexpression of Twist1 increased susceptibility to stress and knockdown of Twist1 via shRNA normalized defective dendrite morphogenesis in the mPFC layer II/III pyramidal neurons and alleviated depressive-like behaviors in the CSDS model. This pro-depressant properties of Twist1 was mediated, in part, through repression of miR-214- peroxisome proliferator activated receptor (PPAR-δ) signaling and mitochondrial function, which was induced after CSDS. We also show that subcutaneous inoculation of 4T1 potentiates depressive-like behaviors in mice through high expression of Twist1 in the mPFC and cancer cells. Conclusion: These findings identify Twist1 in mPFC as a critical mediator of the altered neuronal morphology and depressive-like behaviors induced by chronic stress and 4T1 cells inoculation, providing a potential therapeutic target in depression, especially the cancer induced depression (CID).